Autocrine Role of Cytokines in Vascular Smooth Muscle

细胞因子在血管平滑肌中的自分泌作用

• 批准号: 7197776
• 负责人: Debbie Beasley
• 金额: $ 36.23万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-02-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7197776
• 关键词: Accounting; Agonist; Antigens; Apolipoprotein E; Arteries; Atherosclerosis; Bacteria; Binding; Blood Vessels; Bone Marrow; CCL2 gene; CD14 gene; Cell Proliferation; Cells; Chlamydophila pneumoniae; Chronic; Complement; Complex; Coronary artery; Dependence; Detection; Disease; Doctor of Philosophy; Double-Stranded RNA; Elements; Endothelial Cells; Escherichia coli; Goals; Grant; Growth; Growth Factor; Human; Immune system; In Vitro; Infection; Inflammation; Inflammatory; Injury; Interleukin-1; Intervention; Laboratories; Ligands; Lipopolysaccharides; Mediating; Mediator of activation protein; Membrane; Modeling; Molecular; Molecular Genetics; Molecular Target; Mus; Natural Immunity; Pathogenesis; Pathway interactions; Pattern; Phenotype; Population; Process; Proliferating; Proteins; RNA; Receptor Activation; Research; Role; Signal Transduction; Smooth Muscle Myocytes; TLR2 gene; TLR3 gene; TLR4 gene; Testing; Thinking; Toll-Like Receptor 1; Toll-like receptors; Vascular Diseases; Vascular Smooth Muscle; Viral; anakinra; atherogenesis; autocrine; base; cell growth; cell type; chemokine; cytokine; in vivo; insight; interleukin-1 receptor type I; macrophage; microbial; monocyte; mouse Smc1l1 protein; mouse Smc1l2 protein; mouse model; necdin; neointima formation; novel; pathogen; receptor; response; vascular smooth muscle cell proliferation

DESCRIPTION (provided by applicant): Atherosclerosis is believed to be an inflammatory disease, and accumulating evidence supports a possible role of microbial products, and the receptors that they activate, in the inflammatory process. Whereas most research has focused on the pro-inflammatory roles of macrophages, research by our laboratory and others has shown that vascular smooth muscle cells (VSMC) can be infected by intracellular bacteria and activated by microbial products, whereupon they produce pro-inflammatory cytokines and chemokines, and proliferate. The long-term objective of this project is to determine the roles of interleukin 1 (IL-1) and Toll-like receptors (TLR) in promoting arterial inflammation and neointima formation in vivo. TLRs are trans-membrane receptors known to be essential in microbial detection and activation of innate immunity. During the preceding grant we found that human and mouse VSMC express TLR2, TLRS, and TLR4, and that activation of these receptors by low levels of their respective microbial agonists (Chlamydia pneumonia , double-stranded RNA (dsRNA), and E. coli lipopolysaccharide (LPS)) induces early and robust expression of monocyte chemo-attractant protein 1(MCP-1). Also, LPS and dsRNA increase intranuclear IL-la levels and stimulate proliferation in human coronary artery SMC. Preliminary findings suggest that endogenous IL-la interacts with necdin, an intranuclear growth suppressor, in human VSMC, and that IL-la and necdin may reciprocally regulate human VSMC proliferation. Therefore, the proposed studies will use selective TLRS and TLR4 agonists' in concert with molecular and genetic approaches to determine the mechanisms involved in TLR-induced cellular proliferation in vitro and in vivo. Three hypotheses will be tested: 1) that TLRS- and TLR4-inducedVSMC proliferation involves IL-la, and its receptor-independent inhibition of the suppressive effects of necdin on cell growth; 2) that dsRNA stimulates proliferation of VSMC by a cell type-specific pathway involving not only TLRS and the adapter molecule TRIP, but also a novel dependence on MyD88; and 3) that TLR4 expressed by resident arterial cells contributes to neointima formation and chemokine expression in vivo. The specific aims are: to determine whether endogenous IL-la promotes VSMC proliferation, and whether this action is mediated by its interactions with necdin and/or with the type IIL-1 receptor; to determine whether TLRS and MyD88-dependent ERK1/2 activation are involved in mediating dsRNA-induced proliferation in VSMC; and to determine whether TLR4 contributes to injury-induced chemokine expression and neointima formation using an endothelial denudation injury model in hypercholesterolemic Apolipoprotein E-deficient mice, and to determine the role of TLR4 expressed by bone marrow-derived and resident arterial cell populations to these responses, by using TLR4 chimeric mice. These studies will provide new insights into the mechanisms whereby microbial agents and TLR ligands in the arterial wall may promote proatherogenic arterial inflammation and cellular proliferation, and thereby may provide new molecular targets for pharmacotherapeutic intervention in human vascular disease.

描述（由申请人提供）：动脉粥样硬化被认为是一种炎症性疾病，越来越多的证据支持微生物产物及其激活的受体在炎症过程中的可能作用。虽然大多数研究都集中在巨噬细胞的促炎作用，但我们实验室和其他人的研究表明，血管平滑肌细胞（VSMC）可以被细胞内细菌感染并被微生物产物激活，因此它们产生促炎细胞因子和趋化因子并增殖。本项目的长期目标是确定白细胞介素1（IL-1）和Toll样受体（TLR）在体内促进动脉炎症和新生内膜形成中的作用。TLR是已知在微生物检测和先天免疫激活中必不可少的跨膜受体。在之前的研究中，我们发现人和小鼠VSMC表达TLR 2、TLRS和TLR 4，并且这些受体被低水平的各自的微生物激动剂（肺炎衣原体、双链RNA（dsRNA）和大肠杆菌）激活。大肠杆菌脂多糖（LPS））诱导单核细胞趋化蛋白1（MCP-1）的早期和稳健表达。此外，LPS和dsRNA增加核内IL-1 α水平并刺激人冠状动脉SMC的增殖。初步发现表明，内源性IL-1 α与人VSMC中的necdin（一种核内生长抑制因子）相互作用，并且IL-1 α和necdin可间接调节人VSMC增殖。因此，所提出的研究将使用选择性TLRS和TLR 4激动剂与分子和遗传方法相结合，以确定TLR诱导的细胞增殖的体外和体内机制。将检验三个假设：1）TLRS和TLR 4诱导的VSMC增殖涉及IL-1 α及其受体非依赖性抑制necdin对细胞生长的抑制作用; 2）dsRNA通过细胞类型特异性途径刺激VSMC增殖，该途径不仅涉及TLRS和衔接子分子TRIP，而且还涉及对MyD 88的新依赖性;和3）由驻留动脉细胞表达的TLR 4有助于体内新生内膜形成和趋化因子表达。具体目标是：确定内源性IL-1 α是否促进VSMC增殖，以及该作用是否由其与necdin和/或与II型IL-1受体的相互作用介导;确定TLRS和MyD 88依赖性ERK 1/2活化是否参与介导dsRNA诱导的VSMC增殖;并确定TLR 4是否导致损伤-在高胆固醇血症载脂蛋白E缺陷小鼠中使用内皮剥脱损伤模型诱导趋化因子表达和新生内膜形成，并通过使用TLR 4嵌合小鼠来确定由骨髓来源的和常驻动脉细胞群体表达的TLR 4对这些应答的作用。这些研究将提供新的见解的机制，即微生物制剂和TLR配体在动脉壁可能会促进动脉粥样硬化的动脉炎症和细胞增殖，从而可能提供新的分子靶点药物干预人类血管疾病。